The invention relates to a solid pharmaceutical form of administration containing a diphosphonic acid, a physiologically compatible salt or hydrate thereof as the active substance and stearic acid as lubricant in the outer phase. The invention also relates to a process for preparing the form of administration.
Pharmaceutical forms of administration of diphosphonic acids are known for treatment of calcium metabolism diseases. Drugs containing these active substances are used for treating hypercalcaemia and also for treating tumor osteolysis resulting from bone metastases. They can also be successfully used for treatment of osteoporosis and resulting pain.
Since the active substances for treating diseases of this kind frequently have to be administered over a long period, oral application is very advantageous since it is usually more acceptable to the patient.
Oral forms of administration are known in the case of some diphosphonic acids and salts thereof. For example EP-B 0 275 468, EP-B 0 625 355 (both Boehringer Mannheim) and WO 93/21907 (Leiras Oy) disclose pharmaceutical preparations containing clodronic acid (dichloromethylene diphosphonic acid) or salts thereof. WO 93/09785 (Procter & Gamble Pharmaceuticals) discloses oral forms of administration of risedronate (the salt of 3-pyridyl-1-hydroxyethylidene-1,1-diphosphonic acid). WO 93/21907 and WO 93/09785 describe oral forms of administration provided with a coating which dissolves only at pH above 5 or 5.5. The aim is to ensure that the forms of administration travel through the stomach and the active principle is released only in the intestinal tract.
The solid forms of administration of diphosphonic acids or salts thereof described in the prior art contain the active substance and selected pharmaceutical adjuvants, with which the active principle must be compatible, in the inner phase and selected pharmaceutical adjuvants in the outer phase, more particularly for ensuring that the preparation can be easily processed in a capsule-filling machine or tablet press. For example EP-B 0 275 468 describes clodronate-containing drugs with a high proportion of 80-95% active substance, a filler content of 2-10% and a lubricant content of 0-5% in the granulate, to which is added an outer phase in the form of a lubricant, preferably magnesium stearate and talcum, in a proportion of 1-5%.
During the development of a capsule or tablet or other solid form of administration, special attention is usually paid to the adjuvants in the outer phase.
The selection and proportion of a suitable lubricant in the outer phase is particularly important, since it has great influence on the physical properties of the forms of administration under development. The choice and proportion determine whether the substance filling the capsule or tablet can be processed without difficulty on a suitable machine over a prolonged period or whether the tablets stick to the compression moulding dies in the machine. Sufficient lubricant must therefore be added to the outer phase. If however the proportion of lubricant is too high, there may be other adverse effects. For example the granulate may become so water-repellent that the resulting drug disintegrates only slowly and the desired dissolution rate (practically complete release of the active substance after 30 minutes) is not reached.
The following known lubricants can be used in the outer phase: magnesium stearate, calcium stearate, talcum, sodium stearyl fumarate, macrogol or hydrogenated esters of fatty acids with glycerine and stearic acid.
For example in EP-B 0 275 468, which describes oral forms of administration for clodronate, magnesium stearate and talcum are together used as a lubricant in the outer phase. EP-B 0 625 355 (Boehringer Mannheim GmbH) discloses magnesium stearate as the only lubricant in the outer phase of clodronate forms of administration. WO 93/21907 (Leiras Oy, clodronate) Example 1, describes the use of talcum and magnesium stearate as a lubricant in the outer phase and stearic acid as a lubricant in the inner phase. WO 93/09785 (Procter & Gamble, risedronate) Example 3, discloses stearic acid lubricant in a proportion of 5.8% by weight relative to the tablet core.
It has been found, however, that particularly when the proportions of active substance are low, the lubricant or the concentrations thereof are not optimum, since dissolution rates of 85% after 30 minutes, indicating uniform and almost complete release of the active substance, are not obtained or else the dissolution rates fall rapidly after stress through heating above room temperature.